Antagonism of the centrally-acting excitatory amino acids (EAA), especially at the N-methyl-D-aspartate (NMDA)-specific receptor complex, is believed to represent a useful approach to the treatment of several CNS disorders, including senile dementia, Alzheimer's disease, Huntingdon's chorea, stroke, hypoglycemia, cerebral palsy, cerebral ischemia, epilepsy, and olivo-ponto-cerebellar atrophy. Two approaches to NMDA-antagonism have been pursued in recent years, namely competitive antagonism of the NMDA receptor and noncompetitive blockade of the NMDA-associated ion channel. To date, noncompetitive antagonists have proved more potent and more orally active than their competitive counterparts in blocking NMDA-induced responses in vivo and in protecting against cell death associated with induced cerebral ischemia.
Data suggest that phencyclidine (PCP) and other related "dissociative anesthetics" noncompetitively antagonize NMDA-induced responses by binding to the NMDA-associated ion channel and blocking ion permeability. Unfortunately, PCP possesses undesirable psychotomimetic side effects and causes ataxia in several animal models. In fact, the separation between a compounds's NMDA-antagonist activity and ataxic activity (often expressed as an "efficacy ratio" of the ED.sub.50 's of these two activities) has been extensively used to evaluate its therapeutic usefulness versus its liabilities. In our studies, PCP is approximately equipotent in its abilities to antagonize NMDA-induced lethality in mice and cause ataxia as measured by the traction reflex deficit model, giving an efficacy ratio (ED.sub.50 /TD.sub.50) of approximately 1.4 (Table 1, infra).
The most potent noncompetitive NMDA-antagonist reported to date is MK-801. Like PCP, MK-801 antagonizes NMDA-induced lethality and protects against cell death in cerebral ischemia models. However, MK-801 competes for the high-affinity PCP binding site in the NMDA-associated ion channel. Furthermore, like PCP, there is no separation between MK-801's ability to antagonize NMDA-induced lethality and cause ataxia (efficacy ratio=0.9, Table 1 infra). In fact, the drug discrimination experiments, MK-801 generalizes for PCP, suggesting that MK-801 may possess PCP-like psychotomimetic side effects.
Dextromethorphan, an over-the-counter antitussive, also noncompetitively antagonizes NMDA-induced responses (Table 1, infra). Its proposed binding site in the ion channel may be different from that shared by PCP and MK-801. While not as potent as PCP and MK-801 in antagonizing NMDA-induced lethality, dextromethorphan shows a better antagonism/ataxia efficacy ratio (2.1). However, dextromethorphan is metabolized to dextrorphan in man. Dextrorphan's efficacy ratio is essentially the same as that for dextromethorphan, but data suggests that dextrorphan may exert its effects by interacting with the high-affinity PCP binding site in the NMDA-associated ion channel. This fact again raises the question of PCP-like psychotomimetic side effects.